ANTICANCER IMMUNOGENIC POTENTIAL OF ONCOLYTIC PEPTIDES: RECENT ADVANCES AND NEW PROSPECTS.

Oncolytic peptides are derived from natural host defense peptides/antimicrobial peptides produced in a wide variety of life forms. Over the past two decades, they have attracted much attention in both basic research and clinical applications. Oncolytic peptides were expected to act primarily on tumor cells and also trigger the immunogenic cell death. Their ability in the tumor microenvironment remodeling and potentiating the anticancer immunity has long been ignored. Despite the promising results, clinical application of oncolytic peptides is still hindered by their unsatisfactory bioactivity and toxicity to normal cells. To ensure safer therapy, various approaches are being developed. The idea of the Ukrainian research group was to equip peptide molecules with a "molecular photoswitch" - a diarylethene fragment capable of photoisomerization, allowing for the localized photoactivation of peptides within tumors reducing side effects. Such oncolytic peptides that may induce the membrane lysis-mediated cancer cell death and subsequent anticancer immune responses in combination with the low toxicity to normal cells have provided a new paradigm for cancer therapy. This review gives an overview of the broad effects and perspectives of oncolytic peptides in anticancer immunity highlighting the potential issues related to the use of oncolytic peptides in cancer immunotherapy. We summarize the current status of research on peptide-based tumor immunotherapy in combination with other therapies including immune checkpoint inhibitors, chemotherapy, and targeted therapy.

[The first experience of fluorescent angiography with indocyanine green in primary esophagoplasty with gastric conduit in patients with malignant tumors of the esophagus]. / Pervyi opyt flyuorestsentnoi angiografii s indotsianinom zelenym pri pervichnoi ezofagoplastike zheludochnym steblem u bol'nykh so zlokachestvennymi opukholyami pishchevoda.

OBJECTIVE: To evaluate the possibilities of intraoperative indocyanine green fluorescein angiography (ICG technology) in primary esophagoplasty by gastric conduit in patients with malignant tumors of the esophagus. MATERIAL AND METHODS: The study included 74 patients. Depending on the localization of the tumor in the esophagus, a Lewis-type or McKeown-type operation was performed. The retrospective group (surgery without the use of ICG technology) included 53 patients who underwent surgery from 2015 to 2020 years.The prospective group (surgery with the use ICG technology) included 21 patients operated on from 2021 to 2023 years. ICG technology was used to assess microcirculation in the gastric conduit during esophagoplasty, as well as to identify the right gastroepiploic artery. RESULTS: The ICG fluorescein angiography technique for assessing microcirculation in the gastric conduit was a simple and easily reproducible procedure. Perfusion of the gastric conduit was regarded as satisfactory in 16 (76%) cases, unsatisfactory in 5 (24%) cases, which required resection of the distal part of the conduit. All cases of poor perfusion were in patients with narrow gastric conduit and neck anastomosis location (McKeown-type operation). Anastomotic leakages occurred in 8 (15%) patients in the retrospective group, 4 (19%) patients in the prospective group (p>0.05). In 4 out of 5 cases of poor gastric conduit perfusion, anastomotic leaks occurred. Immediate postoperative results in the compared groups were also comparable. The use of ICG technology in 5 (45%) cases out of 11, when laparoscopic mobilization of the stomach was performed, helped to visualize the right gastroepiploic artery, which is the main source of blood supply to the formed gastric conduit. The use of ICG technology in 3 patients with a compromised gastrostomy stomach demonstrated the absence of significant microcirculation disorders in the stomach wall. CONCLUSION: The first experience of using fluorescein angiography with ICG in primary esophagoplasty by gastric conduit in patients with malignant tumors of the esophagus demonstrated the safety, simplicity and availability of this technique. An objective assessment of the effectiveness of the application of ICG technology requires the accumulation of experience.

[The rare diseases and orphan medications: Placement in health care of the Russian Federation].

The rare diseases are characterized both by relatively small prevalence in population and complexity of medical care support of patients. In this particular case, the legal regulation of medical care takes its particular placement in health care. The uniqueness of rare diseases requires development of special normative legal acts, definitions and treating approaches. One of such approaches are orphan drugs that also are unique, complicated in development and require special legislative regulation. The article presents corresponding legislative terminology in modern Russian health care, actual listings of rare diseases and orphan drugs. The directions to improve current terminology and normative legal regulation are proposed.

[The characteristics of restrictive listings of medications: the position of orphan medical preparations].

In the Russian Federation, the regulations on making out restrictive listings of medications were established as separate Government Order in 2014. Since this moment, the procedure of listing revision underwent various changes. The last revisions of this legal document contained several amendments regarding orphan medications. So, in last version the rating scale included separate component related to these medications. This indicates at unique characteristics of orphan medications that not allow to consider them along with other medications. The article covers main stages of drug list forming procedures of making out restrictive listings of medications in the light of how available methodology is adapted to be applied to orphan medications.

JCV seroconversion rate during the SARS COVID-19 pandemic.

The transmission route of the John Cunningham virus (JCV) is not clearly understood. The high prevalence of JCV in urine and sewage and the stability of the viral particles observed suggest that contaminated water, food, and fomites could be the vehicles of JCV transmission through the oral route. Multiple Sclerosis (MS) patients treated with Natalizumab are at risk of developing progressive multifocal leukoencephalopathy (PML), and hence, JCV serology is monitored for risk stratification. Social restrictions introduced in 2020 which intended to limit the transmission of SARS-CoV-2 are associated with decreased rates of other communicable diseases, as has been shown in recent observational studies. We evaluated the prevalence of seroconversion prior to and during the coronavirus disease (COVID -19) pandemic based on clinical records of JCV serology status in a single-center cohort of Natalizumab-treated Multiple Sclerosis patients. We hypothesized that seroconversion rates would decrease due to behavioral changes. However, seroconversion rates were stable during the COVID-19 pandemic compared to the pre-pandemic. These findings support the notion that JCV is transmitted via the GI tract rather than the respiratory system.

[The intermediate outcomes of delegation of obligations of medicinal support of patients with rare diseases to the Federal level in 2019-2020].

Lately, in case of a number of life-threatening and chronic progressive rare (orphan) diseases, resulting in decreasing of life expectancy of citizens or their disability, the powers to support patients with medications were transferred from regional to federal level. Among these diseases are hemolytic uremic syndrome, mucopolysaccharidose type I, II, VI, juvenile arthritis with systemic onset, unspecified aplastic anemia, hereditary deficiency of factors II (fibrinogen), VII (labile), X (Stuart-Prauer). The article considers data concerning hemolytic uremic syndrome, mucopolysaccharidosis type I, II, VI, juvenile arthritis with systemic onset - the diseases for which medication support provision was transferred to Federal level in the first place and for which at the time of preparation of the article there were sufficient data to analyze.

Punzi-loss:: a non-differentiable metric approximation for sensitivity optimisation in the search for new particles.

We present the novel implementation of a non-differentiable metric approximation and a corresponding loss-scheduling aimed at the search for new particles of unknown mass in high energy physics experiments. We call the loss-scheduling, based on the minimisation of a figure-of-merit related function typical of particle physics, a Punzi-loss function, and the neural network that utilises this loss function a Punzi-net. We show that the Punzi-net outperforms standard multivariate analysis techniques and generalises well to mass hypotheses for which it was not trained. This is achieved by training a single classifier that provides a coherent and optimal classification of all signal hypotheses over the whole search space. Our result constitutes a complementary approach to fully differentiable analyses in particle physics. We implemented this work using PyTorch and provide users full access to a public repository containing all the codes and a training example.

[The normative legal regulation of medical care support of rare (orphan) diseases in adult population of The Russian Federation].

The article considers the results of legal regulation analysis of medical care support including medication maintenance of adult patients suffering from rare diseases exemplified by life-threatened and chronic progressed rare (orphan) diseases resulting in life expectancy decrease and or disability ("List-24"). MATERIALS AND METHODS: Law database was analyzed in terms of current orders of medical care provision, standards of medical care, and clinical guidelines for rare diseases from "List-24" regarding to adult patients. RESULTS: It is concluded that there are no determined rules of medical care provision to adult population in case of rare diseases from "List-24". There are standards of medical care on 6 rare diseases (25% of total diseases amount) from this list for adult patients. However, based on content analysis data of approved standards it was established that there are only 3 from 11 standards (27.28%) for primary medical care support, 4 standards (33.34%) for medical care provision in planned condition, and only 1 standard (9.09%) had appropriate legal basis for its development (clinical guidelines availability). Nevertheless, there is negative prognosis for this the only standard due to legal necessity of all clinical guidelines revision till the end of 2021. CONCLUSION: Revision and creation of clinical guidelines and standards of medical care afterwards are needed for adult patients treatment with rare diseases from "List-24". The conclusion was made in terms of medical care standardization improvement for adult patients suffering from rare diseases from "List-24" based on its alignment with current legal regulation.

[The analysis of detection of rare diseases not included into listings of orphan diseases with preferential medication support].

The study was carried out to analyze detection of rare diseases that are not included into listings of rare (orphan) diseases to be treated at the expense of budget resources of the Russian Federation Russian Federation (hereinafter referred as rare diseases out of reimbursement). The analysis of detection of patients with rare diseases out of reimbursement in Russian Federation was carried out. The information was collected and summarized on the basis of open sources by the way of formalized personal request to the heads of patient and public organizations providing care of patients with rare diseases out of reimbursement. It is established that in the Russian Federation (85 subjects) reside patients with more than 250 forms and groups of rare diseases and only 28 out of them are included into the Federal registries of patients. Actually, there are more than 8 000 nosologic forms of rare diseases that are known thus far. The monitoring permitted to collect data concerning 30 particular nosological forms and groups of rare diseases out of reimbursement. Among them, 23 out of 30 analyzed pathologies have genetic nature. And only for 24 out of 30 diseases the registration of patients is applied. It is necessary to organize modern system of registration of patients within the framework of the Federal registry that includes full and actual data about patients, course of disease, therapeutic interventions that will permit to determine prevalence, disability, mortality, lethality, necessary medicinal maintenance and also to establish spectrum of diseases that are to be included into drug reimbursement programs.

[Results of complex treatment of patients with thoracic esophageal cancer].

In the open, comparative, non-randomized and prospective study conducted from 2007 to 2014 there were included 83 patients who received combined treatment for thoracic esophageal cancer. For a comparative analysis there was used a retrospective control group of 51 patients with esophageal cancer who had undergone surgery alone from 1999 to 2014. Complex treatment of patients with advanced forms of thoracic esophageal cancer included argon-plasma recanalization of the lumen of the esophagus followed by neoadjuvant chemoradiotherapy in two versions. One group of patients (29) received external beam radiotherapy, prescription dose of 40-45 Gy, the other group of patients (54) received intraluminal brachytherapy, 3 sessions of 7 Gy, prescription dose of 21 Gy. All patients synchronously with radiotherapy there were performed two cycles of polychemotherapy on PF scheme. A month after the neoadjuvant treatment there was carried out resection of the esophagus with simultaneous plastics by gastric stem. Complete local tumor regression was achieved in 34,7% of patients in group with intraluminal brachytherapy and 30% in the group with external beam radiotherapy. Long-term results could be traced in 90.8% of patients. Using chemoradiotherapy on preoperative stage we managed to increase disease-free and overall survival of patients with an increase of median of progression-free survival - 27 against 12 months and overall survival - 29 against 14 months in comparison with surgery alone.

[Technological Perspectives in Developing Carbon Nanotube-based DNA-modified Biosensors].

In this research we investigated the response of DNA-modified carbon nanotubes in the presence of thrombin and albumin. We analyzed aptamer-carbon nanotube interactions by Raman spectroscopy and by analyzing resistance after each step of biosensor assembly. We have shown that intensity of G-band decreases due to interconnection of aptamer and carbon nanotube and this also evaluates in decrease of sensor structure resistance. The response of the sensor exposed to thrombin and albumin differs essentially from each other. This fact serves as the prerequisite for the development of a highly selective biosensor. Results of this investigation can be used in creation of new generation of personal health monitoring systems.

[MINIMALLY INVASIVE ESOPHAGECTOMY].

During the period from April 2012 to December 2014 54 patients aged 29-76 years, 36 (66.6%) males and 18 (33.4%) females, with esophageal cancer underwent minimally invasive esophagectomy as final phase of treatment. Squamous cell carcinoma was diagnosed in 50 patients and adenocarcinoma identified in 4 patients. The disease was staged as follows: IA--5 (9.3%) patients, IB--11 (20.4%) patients, IIA-- (16,.%) cases, III -- (3,.%) cases, IIII --8 (33,.%), IIII -- (14,8%), III -- (1,.%). 37 (68,.%) patients had surgery after induction chemoradiation therapy. Of 54 surgical interventions there were 20 hybrid and 34 minimally invasive operations. 19 (35,.%) patients developed complications, postoperative mortality was 2 (3,.)%. Minimally invasive esophagectomy meets basic oncological principles and leads to tolerable short-term results.

[Mini-invasive technologies in complex treatment of esophagus cancer].

It was evaluated mini-invasive endovideosurgical technologies using in complex treatment of esophagus cancer. The investigation included 28 patients with thoracic esophagus cancer. Age of patients operated in terms from April 2012 to December 2013 was from 42 to 74 years (mean 61.7 ± 8.7 years). Only surgical treatment was used in 10 patients. Neoadjuvant chemotherapy and radiotherapy were performed in 18 patients. Hybrid mini-invasive esophagectomy (laparoscopic stomach mobilization and right-side thoracotomy) were used in 14 cases. The frequency of postoperative complications was 35.5%. Mini-invasive endovideosurgical esophagectomy was done in 14 patients. The frequency of postoperative complications was 57.1%. There were not deaths. Our experience demonstrates good results of mini-invasive technologies using in treatment of patients with esophagus cancer. Endovideosurgical methods permit to perform adequate volume of surgery in case of oncological diseases.

[Immediate and long-term results of brachytherapy in complex treatment for esophageal cancer].

For treatment of cancer of the thoracic esophagus, the method of neoadjuvant chemoradiotherapy (CRT) with a use of intraluminal brachytherapy (BT) was performed. The study included 51 patients (mean age 56.9 ± 4.3 years). The length of the primary tumor up to 6 cm was determined in 18 patients, more than 6 cm--33 patients. CRT included three BT sessions (7Gy X 3; q7d) and two cycles of chemotherapy (PF; q28d). After CRT in 30 (62.4%) patients there was marked a complete or partial radiological tumor regression. In 40-45 days after CRT surgery performed. Subtotal resection of esophagus of the Lewis type was performed in 29 cases, transtracheal ex- tirpation of the esophagus--in 2, minimally invasive esopha- gectomy--in 17 cases. Postoperative complications occurred in 22 (44%) patients; one patient died (2%). In 11 (23%) patients morphological investigation revealed a complete regression of the primary tumor. Thus, a use of intraluminal BT in combination with chemotherapy in many cases promoted reducing the size of the primary tumor of the esophagus, which was an effective factor in improving surgical results.

[Experience of the use of endovideotechnology in surgical treatment of esophageal cancer].

An investigation included 33 patients with cancer of thoracal section of the esophagus at the age from 42 to 74 years old. A surgical method of treatment was applied as only one in 13 patients and methods of nonadjuvant chemoradiation therapy were used for 20 patients. A hybrid minimally invasive esophagectomy (laparoscopic mobilization of the stomach and right-side thoracotomy) was performed on 16 patients. The rate of postoperative complications consisted of 31%. The minimally invasive esophagectomy (performed by totally endovideosurgical approach) was carried out in 15 cases. Postoperative complications developed in 53% of follow-up patients. There weren't cases of lethality. The experience of minimally invasive methods indicated the satisfactory results of application of given methods in patient treatment of esophageal cancer. The use of endovideosurgical approaches allowed performing oncologically adequate volume of operative interventions.

[Concurrent chemoradiotherapy with moderate dose brachytherapy as remission induction for patients surgically treated for esophageal cancer].

The locally advanced cancer of thoracic esophagus was treated by induction chemo-irradiation therapy (IHRT) with intraluminal medium dose-rate brachytherapy (IMBT). From July 2009 to February 2012 twenty five patients (mean age 54.3 +/- 1.3 years) were included in the study. The length of the primary tumor was up to 6 cm in 10 pts and more than 6 cm in 15 pts. Induction therapy consisted of three IMBT sessions (7 Gy X 3; q7d) and two cycles of chemotherapy (PF; q28d), 26-31 days later the surgery was performed. Subtotal resection of the esophagus type of I Lewis was performed in 23 pts, transtracheal extirpation of the esophagus was performed in 2 pts.In all the cases 3F lymphodissection was performed. After IHRT in 15 of 25 pts. was obtained complete or partial response, in 10 of 25 pts was obtained disease stabilization. Perioperative complications occurred in 17 (68%) patients receiving conservative treatment, one patient (4%) died of treatment complications. In 6 cases (24%) morphology had shown the complete regression of primary tumor. Thus, the combination of intraluminal medium dose-rate brachytherapy and chemotherapy lead to reduction of primary tumor local spread and can be an efficient factor in improving the results of surgical treatment.